Pramipexole transdermal delivery system and uses thereof

ABSTRACT

A pramipexole transdermal patch for treatment of neurological disorders including Parkinson&#39;s disease that may be administered on a daily basis. The pramipexole transdermal patch of the present invention preferably comprises a drug-containing layer that comprises pramipexole or a pharmaceutically acceptable salt thereof at 2% to about 15% by weight of the drug-containing layer and at least two acrylic polymers wherein each polymer may further comprise carboxyl and/or hydroxyl functional groups. The pramipexole transdermal patch of the present invention may further comprise two or more permeation enhancers with combined pramipexole solubility of great than 50 mg/mL.

CROSS-REFERENCE TO RELATED APPLICATION(S)

The present application is a continuation application to PCT/US16/55866with filing date of Oct. 7, 2016 entitled “Pramipexole TransdermalDelivery System and Uses Thereof.”

FIELD OF THE INVENTION

The present invention relates to a pramipexole transdermal patch. Morespecifically the present invention relates to a pramipexole transdermalpatch for daily administration, method of making and use thereof.

BACKGROUND OF THE INVENTION

Parkinson's disease (PD) is a chronic and progressive neurodegenerativedisorder with symptoms such as resting tremor, rigidity, bradykinesiaand postural instability. These symptoms are largely caused byprogressive loss of dopaminergic neurons in the substantia nigracompacta, which ultimately reduces dopaminergic input to the striatumand other brain regions.¹ Medications for treating PD symptoms aretypically orally administered in the form of tablets or capsulescontaining active pharmaceutical ingredient levodopa or pramipexoleamongst others such as ropinirole, amantadine, catechol-omethyltransferase (COMT) inhibitors, rasagiline, rotigotine and biperidine. ¹Ferrer I, Martinez A, Blanco R, Dalfo'E, Carmona M (2011) Neuropathologyof sporadic Parkinson disease before the appearance of parkinsonism:preclinical Parkinson disease. J Neural Transm 118: 821-839

Levodopa (L-dihydroxyphenylalanine or L-dopa) is a dopamine precursorwhich is administered with carbidopa, a dopa-decarboxylase (DDC)inhibitor, so that the levodopa is decarboxylated substantially withinthe central nervous system. However, with extended use of levodopa,fluctuations in motor control can occur with increasing frequency andseverity, eventually disabling the patient.

Pramipexole is a member of the class of drugs known as dopamine agoniststhat may be administered concurrently with levodopa to help alleviatethe fluctuations in motor control. Dopamine agonists (DAs) are syntheticagents which directly stimulate dopamine receptors and are used eitherin monotherapy for the treatment of the motor symptoms of PD in theearly stage of the disease or in the later phase of the disease tolessen motor complications associated with levodopa therapy.

Although PD medications are typically in the form of tablets andcapsules, transdermal patches offer an alternative form ofadministration. Specifically, compared to tablets and capsules,transdermal patches provide reduced dosing frequency, prolongedtherapeutic duration, avoidance of gastrointestinal absorption as wellas hepatic first-pass metabolism, minimized fluctuation in plasma drugconcentrations, noninvasive administration with advantages over the oralroute of administration, easy termination of drug administration bysimply removing the patch from the skin and improved patientcompliance.^(2, 3) ² Prausnitz M, Langer R., Transdermal drug delivery,Nat Biotechnology. 2008 November; 26(11): 1261-1268³ Gaikwad A.,Transdermal drug delivery system: Formulation aspects and evaluation,Comprehensive Journal of Pharmaceutical Sciences. February 2013, Vol.1(1), pp. 1-10

With respect to improved patient compliance, the transdermal patch isparticularly beneficial to PD patients in comparison to tablets orcapsules. The reason is that PD tablets and capsules require multipledaily doses in contrast with the transdermal patch which is capable ofproviding prolonged therapeutic duration with just one singleapplication, simplifying dosing regimen and, thereby, facilitatingpatient compliance. In addition, a patient can easily forget whether heor she has already taken a capsule or tablet whereas, in contrast, apatient can easily tell whether a new transdermal patch has beenapplied, making it easier for a patient to follow required dosingregimen. Dosing regimen compliance in the patients with PD isparticularly important since PD is a progressive, neurological diseasethat requires lifelong treatment. The simplified drug regimen wouldsubstantially improve the quality of life of the PD patients as well astheir caregivers.

Published patent applications CN 103432104, Tingting Pu et al. AAPSPharma Sci Tech 2016 published online May 31, 2016 and US 2016/0113908,the disclosures of which are incorporated herein by reference, eachdisclose pramipexole transdermal patches applied for therapeuticduration over multiple days use, the former two references describinguse over a five to seven day period per patch application while thelatter US publication describes a therapeutic use ranging from at leasttwo days through one hundred sixty eight hours (seven days) per patch.This publication also references in paragraph 0073 that the acrylic baseadhesive is preferably based on acrylates lacking a carboxylic acidfunctional group.

Although week-long pramipexole transdermal patches provide substantiallysimpler dosaging regimen in comparison to tablets and capsules, theprolonged therapeutic duration can itself create challenges. Forexample, a week-long pramipexole transdermal patch requires high drugloading that increases potential risks with respect to toxicity and dosedumping. In addition, by design, the high drug loading and prolongedtherapeutic duration dictate that the patches do not allow moisture topass through since moisture enhances the likelihood of pramipexolecrystallization. A transdermal patch on a patient's skin that does notpermit for moisture pass through for a days at a time may cause skinirritation that may become severe.⁴ Moreover, from a practical point ofview, requiring a transdermal patch to be applied to the skin for daysat a time may also be an obstacle in the way of a patient's other dailyneeds such as showers or baths. Therefore, a pramipexole transdermalpatch with therapeutic duration of about 24 hours, or a dailypramipexole transdermal patch, may provide advantages for administeringpramipexole not only as compared to tablets and capsules but alsocompared to transdermal patches of week-long duration. ⁴ Paude K.,Milewski M., Swadley C., Brogden N., Ghosh P. and Stinchcomb A.,Challenges and opportunities in dermal/transdermal delivery, NIH PublicAccess; 2010 Jul. 1{grave over ( )} (1): 109-131

There exists a commercially available transdermal patch for dailyadministration that provides a dopamine agonist for treating PD calledNeupro® transdermal patch that contains rotigotine as the activepharmaceutical ingredient. However, it has been reported thatrotigontine presents a higher risk of hypotension and somnolence incomparison with pramipexole.⁵ In addition, U.S. Pat. No. 7,344,733refers to transdermal pramipexole and ropintrole patches and referencesproduct deficiencies of a pramipexole patch described in EP-B1-0 428 038in terms of very rapid decomposition of the active ingredientaccompanied by discoloration and the pramipexole crystallization. The'733 patent describes the use of acrylate monomer adhesives alone orpolymerized with functional monomers. However, none of the listedacrylates use adhesive admixtures contain both a functional hydroxyl andcarboxylic acid group. ⁵ Etminan M, Gill S and Samil A., Comparison ofthe risk of adverse events with pramipexole and ropinirole in patientswith Parkinson's disease: a meta-analysis, Drug Saf, 2003; 26(6):439-44

Therefore, it is an object of the invention to provide a pramipexoletransdermal patch for daily administration with minimal pramipexoleblood concentration fluctuations. It is another object of the inventionto provide a pramipexole transdermal patch with high flux and lowpramipexole crystallization.

SUMMARY OF THE INVENTION

The present invention provides a transdermal patch for treatingParkinson's disease comprising a drug-containing layer, a backing layerand a protective layer wherein the drug-containing layer comprisespramipexole or a pharmaceutically acceptable salt thereof and two ormore polymers wherein at least two of the polymers each furthercomprises a carboxyl functional group and/or a hydroxyl functionalgroup. In some embodiments, the pramipexole or its pharmaceuticallyacceptable salt thereof comprises pramipexole free-base, pramipexoledihydrochloride or dexpramipexole. In another embodiment, thepramipexole or its pharmaceutically acceptable salt thereof is in anamount from about 2% to about 15% by weight of the drug-containinglayer. In yet another embodiment, the at least two polymers comprisestwo acrylate-based polymers. In some embodiments, the acrylate-basedpolymers comprise a carboxyl group-containing acrylic-based polymer anda hydroxyl group-containing acrylic-based polymer. In other embodiments,the carboxyl group-containing acrylic-based polymer is sourced from asolution of cross-linked acrylates copolymer comprising acrylic acid and2-ethylhexyl acrylate. In yet other embodiments, the hydroxylgroup-containing acrylic-based polymer is sourced from a polymersolution of acrylates copolymer comprising 2-hydroxyethyl acrylate orfrom a polymer solution of acrylates copolymer comprising vinyl acetateand 2-hydroxyethyl acrylate. In some embodiments, the carboxylgroup-containing acrylic-based polymer and the hydroxyl group-containingacrylic-based polymer are in a ratio of from about 2:1 to about 1:2 byweight.

In some embodiments, the drug-containing layer further comprises acombination of two or more permeation enhancers. In other embodiments,the combination of two or more permeation enhancers has pramipexolesolubility of above about 50 mg/mL. In yet other embodiments, the two ormore permeation enhancers comprise fatty acids, fatty alcohols, solventand/or surfactants. In some embodiments, the two or more permeationenhancers comprise aliphatic alcohols, fatty acids having chain of 8 to20 carbons, fatty acid esters, alcohol amines, polyhydric alcohol alkylethers, polyoxyethylene alkyl ethers, glycerides, middle-chain fattyacid esters of polyhydric alcohols having chain of 8-20 carbon atoms,alkyl esters having chain of 1-6 carbon atoms, acylated amino acids,pyrrolidone, pyrrolidone derivatives, ethoxylated fatty alcohols,surfactants or a combination thereof.

In some embodiments, the transdermal patch of the present inventionprovides flux rate of more than about 0.8 μg/cm² hr and less than about10 μg/cm² hr for up to about 40 hours. In other embodiments, lag timefor the transdermal patch of the present invention is less than about 8hours.

The present invention also provides for a method for treating aneurological disorder comprising the step of administering thetransdermal patch of the present invention to a human subject in needthereof through the human's skin for a period of about 24 hours. Inother embodiments, the total delivered amount of pramipexole is fromabout 0.2 mg to about 10 mg daily. In yet other embodiments, theneurological disorders comprise Parkinson's disease, Restless LegSyndrome, migraine headaches, or ALS

DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrate in vitro cumulative permeated pramipexole in mg/cm²versus time in hours for 30 hours for transdermal patches made from DuroTak 87-2852, Duro Tak 87-2510, Duro Tak 87-2054 and Duro Tak 87-4287,respectively.

FIG. 2 illustrate in vitro influence of permeation enhancers onpramipexole permeation. The figure shows cumulative permeatedpramipexole amount in mg/cm² versus time in hours for about 30 hours forformulations F6-32 and F6-34, wherein the two formulations differ onlyin the selection of the permeation enhancers. For example, F6-32comprises a combination of methyl laurate and propylene glycolpermeation enhancers whereas F6-34 comprises a combination of methyllaurate and Brij 30 permeation enhancers.

FIG. 3 illustrate pramipexole plasma concentration profile in ng/mLversus time in hours over the first 48 h after administration offormulations F6-20 and F6-24 as well as the reference Sifrol® 0.375 ERtablet.

DETAILED DESCRIPTION OF THE INVENTION

As used in this specification and in claims which follow, the singularforms “a”, “an” and “the” include plural referents unless the contextclearly indicates otherwise. Thus, for example, reference to “aningredient” includes mixtures of ingredients, reference to “an activepharmaceutical agent” includes more than one active pharmaceuticalagent, and the like.

The terms “active agent”, “pharmacologically active agent” and “drug”are used interchangeably herein to refer to a chemical material orcompound that includes a desired pharmacological, physiological effectand include agents that are therapeutically effective. The terms alsoencompass pharmaceutically acceptable, pharmacologically activederivatives and analogs of those active agents specifically mentionedherein, including, but not limited to, salts, esters, amides, prodrugs,active metabolites, inclusion complexes, enantiomers S(−) or R(+) (seeU.S. Pat. No. 8,445,474, the disclosure which is incorporated herein byreference), analogs and the like.

As used herein, the term “about” as a modifier to a quantity is intendedto mean + or − 10% inclusive of the quantity being modified.

As used herein, the term “aliphatic” refers to a non aromatichydrocarbon in which the carbon atoms are either straight or branchchain or cyclic and either saturated or unsaturated.

The term “effective amount” or “a therapeutically effective amount” of adrug or pharmacologically active agent is intended to mean a nontoxicbut sufficient amount of the drug or active agent for providing thedesired therapeutic effect. The amount that is “therapeuticallyeffective” will vary from subject to subject, depending on the age andgeneral condition of the individual, the particular active agent oragents, and the like. An appropriate “therapeutically effective” amountin any individual case may be determined by one of ordinary skill in theart using routine experimentation.

The term “transdermal patch” is intended to refer to a self-contained,discrete dosage form that, when applied to skin, is designed to deliverthe drug(s) through the skin into systemic circulation. Some importantcharacteristics of a transdermal patch include flux rate, lag time andstability. Flux rate relates to the rate at which the transdermal patchdelivers pramipexole. Lag time relates to the time required forpramipexole blood concentration to reach steady state after applicationof the transdermal patch. Lag time preferably matches pramipexolemetabolization rate in order to minimize fluctuations in bloodconcentration between applications of successive transdermal patches.Lastly, stability relates to the amount of impurities that developswithin the transdermal patch while in storage.

Flux rate and lag time differ substantially for a daily transdermalpatch as compared to a week-long pramipexole transdermal patch. Thereason is that administration of daily transdermal patch by definitionrequires interruption of drug delivery once a day, so when a replacementdaily transdermal patch is applied, the new patch needs to providehigher flux rate and shorter lag time to quickly ramp up delivery ofpramipexole to the patient in order to maintain constant pramipexoleblood concentration while minimizing blood concentration fluctuation.Specifically, the daily pramipexole transdermal patch preferablyprovides a steady state flux rate at about 0.8 μg/cm² hr and up to about13 μg/cm² hr as well as a lag time of less than about 8 hours.

Further differences between the daily and weekly pramipexole transdermalpatch is that the daily transdermal patch of the present invention isable to tolerate moisture in contrast with week-long pramipexoletransdermal patches. Tolerance for moisture is possible for the dailytransdermal patch of the present invention because it contains lowerdrug loading and has substantially shorter therapeutic duration thanweek-long patches. In addition, the lower drug loading also allowssmaller patch size than the week-long patches. For example, in oneembodiment, the daily pramipexole transdermal patch of the presentinvention may be about 30 cm² or less. The tolerance for moisture andsmaller patch size both help to reduce risks for and severity of skinirritation.

The pramipexole transdermal patch of the present invention comprises adrug-containing layer that comprises pramipexole free base or apharmaceutically acceptable salt thereof as the active pharmaceuticalingredient. The pramipexole or the pharmaceutically acceptable saltthereof may comprise pramipexole free base, pramipexole dihydrochlorideor dexpramipexole

The pramipexole drug-containing layer of the transdermal patch of thepresent invention further comprises one or more polymers for housingpramipexole that play a significant role in determining pramipexole fluxrate. Specifically, higher flux rate may be achieved by lowering thesolubility of the pramipexole within the polymer(s) relative to thesolubility within the stratum corenum layer of the user's skin.⁶However, low solubility of pramipexole can cause crystallization ofpramipexole within the skin patch, reducing the amount of pramipexoleavailable to be delivered to a user. ⁶ J. W. Wiechers, C. I., Kelly, T.G. Blease and J. C. Dederen, Formulating for Efficacy, InternationalJournal of Cosmetic Science, 2004, 26, 173-183

In addition, low solubility of respective ingredients of the transdermalpatch, or low miscibility, could present manufacturing issues as itcould prevent even distribution of pramipexole within the polymers andcause phase separation.

Therefore, solubility of pramipexole within the polymers and miscibilityof respective components of the transdermal patch are importantconsiderations that necessitate proper balancing when selecting polymersand creating formulations using the selected polymers for thetransdermal patch of the present invention.

One possible class of polymers for use in the pramipexole transdermalpatch of the present invention is acrylate-based polymers.Acrylate-based polymers are used extensively in transdermal drugdelivery systems since they are relatively low in cost compared to otherpolymers, provides high solubility for a variety of drugs includingpramipexole and pharmaceutically acceptable salt thereof, adhere well toa variety of different surfaces and capable of being formulated toprovide adhesive property.

Acrylate polymers may comprise copolymers of various monomers which maybe “soft” monomers or “hard” monomers or combinations thereof. Softmonomers are characterized by having lower glass transition temperature.Examples of soft monomers include, but not limited to, n-butyl acrylate,2-ethylhexyl acrylate and isooctyl acrylate. Hard monomers arecharacterized by having higher glass transition temperature. Examples ofhard monomers include, but not limited to methyl methacrylate, ethylacrylate and methyl acrylate. Soft monomers with lower glass transitiontemperature generally have higher solubility and better stabilitycompared to hard monomers.

Monomers from which the acrylate polymers may be produced may compriseacrylic acid, methacrylic acid, butyl acrylate, butyl methacrylate,hexyl acrylate, hexyl methacrylate, isooctyl acrylate, isooctylmethacrylate, glycidyl methacrylate, 2-hydroxyethyl acrylate, methylacrylate, methylmethacrylate, 2-ethylhexyl acrylate and 2-ethylhexylmethacrylate. Additional examples of acrylic adhesive monomers aredescribed in Satas, “Acrylic Adhesives,” Handbook of Pressure-SensitiveAdhesive Technology, 2nd ed., pp. 396-456 (D. Satas, ed.), Van NostrandReinhold, New York (1989).

Acrylate polymers may comprise bipolymer, terpolymer or tetrapolymer orcopolymers of even greater numbers of monomers, including copolymers ofalkyl acrylates, alkyl methacrylates, coploymerizable secondary monomersand/or monomers having functional groups.

In addition, the acrylic-based polymers may have hydroxyl functionalgroup and/or carboxyl functional groups which can influence propertiesof the polymers such as solubility of pramipexole, miscibility withother components of the transdermal patch as well as pramipexole fluxrate. The influence of functional groups is polymer dependent, andtherefore, difficult to predict.

Moreover, the acrylic-based polymers may also contain cross-linkers thatprovide chemical bonds between polymer chains so as to mitigate coldflow within the transdermal patch of the present invention. In someembodiments, the cross-linkers comprise about 0.01% to about 6% byweight of the drug-containing layer. Examples of cross-linkers that maybe used with acrylic-based polymers containing hydroxyl functional groupinclude but are not limited to polybutyl titanate (PBT), tetrabutyltitanate (TBT), titanium dialkoxide bis(acetylacetonate) and/or titaniummetal chelate. Examples of cross-linkers that may be used withacrylic-based polymers containing carboxyl functional group include butare not limited to aluminum tris(acetyl acetonate) and/or aluminiummetal chelate. In addition, the acrylic-based polymers may be combinedwith tackifiers to provide adhesive property.

Examples of commercially available acrylic-based polymer that areacrylic-hydrocarbon hybrid polymers may be sourced from polymersolutions including, but not limited to, Duro-Tak™ 87-502B and Duro-Tak™87-504B, Duro-Tak™ 87-502A, Duro-Tak™ 87-503A and Duro-Tak™ 87-504A.Examples of acrylate-based polymers with no functional group may besourced from polymer solutions including, but not limited to, Duro-Tak™87-4098, Duro-Tak™ 87-900A and Duro-Tak™ 87-9301. Examples ofacrylate-based polymers having carboxyl functional group may be sourcedfrom solutions including, but not limited to, Duro-Tak™ 87-235A,Duro-Tak™ 87-2353, Duro-Tak™ 87-2852, Duro-Tak™ 87-2051, Duro-Tak™87-2052, Duro-Tak™ 87-2054, Duro-Tak™ 87-2194 and Duro-Tak™ 87-2196.Examples of acrylate-based polymers having hydroxyl functional group maybe sourced from solutions including, but not limited to Duro-Tak™87-2510, Duro-Tak™ 87-2287, Duro-Tak™ 87-4287 and Duro-Tak™ 87-2516.Examples of acrylate-based polymers having both hydroxyl and carboxylfunctional groups may be sourced from solution including, but notlimited to Duro-Tak™ 87-2074 and Duro-Tak™ 87-2979.

TABLE 1 Typical Physical Properties Contains Viscosity vinyl Contains(cP or Product Description acetate Crosslinker Solids (%) mPa-s)Duro-Tak 87-900A acrylates copolymer No n/a 43 1800 Duro-Tak 87-9301acrylates copolymer No n/a 36.5 9500 Duro-Tak 87-4098 acrylatescopolymer Yes n/a 38.5 6500 Duro-Tak 87-2510 acrylates copolymer No No40.5 4250 Duro-Tak 87-2287 acrylates copolymer Yes No 50.5 18000Duro-Tak 87-4287 acrylates copolymer Yes No 39 8000 Duro-Tak 87-2516acrylates copolymer Yes Yes 41.5 4350 Duro-Tak 87-2074 acrylatescopolymer No Yes 29.5 1500 Duro-Tak 87-235A acrylates copolymer No No36.5 8000 Duro-Tak 87-2353 acrylates copolymer No No 36.5 8000 Duro-Tak87-2852 acrylates copolymer No Yes 33.5 2500 Duro-Tak 87-2051 acrylatescopolymer Yes No 51.5 4000 Duro-Tak 87-2052 acrylates copolymer Yes Yes47.5 2750 Duro-Tak 87-2054 acrylates copolymer Yes Yes 47.5 2750Duro-Tak 87-2194 acrylates copolymer Yes Yes 45 3000 Duro-Tak 87-2196acrylates copolymer Yes Yes 45 2100 Duro-Tak 87-2979 acrylates copolymerYes — 44.5 2700 Duro-Tak 87-2825 acrylates copolymer Yes — 47.5 1650Duro-Tak 87-2525 acrylates copolymer Yes — 41.5 4350

Experiments were performed to evaluate the solubility of pramipexole invarious polymers with results listed in Table 2 with experiment detailedin Example 1 below. We found that solubility of below 5% would preventproper distribution of pramipexole within the transdermal patch. Amongthe polymers tested, the carboxyl and hydroxyl groups-containing acrylicpolymer sourced from Duro-Tak 87-2979, the carboxyl group-containingacrylic polymer sourced from Duro-Tak 87-2054 and the hydroxylgroup-containing acrylic polymer sourced from Duro-Tak 87-2510 andDuro-Tak 87-4287 provided adequate solubility.

TABLE 2 Functional API Adhesive Description group solubility DURO-TAK87-2979 acrylate-vinylacetate —COOOH/ 10% —OH DURO-TAK 87-2054acrylate-vinylacetate —COOH 10% DURO-TAK 87-2510 Acrylic —OH 5% DURO-TAK87-4287 acrylate-vinylacetate —OH 8%

In order to take advantage of desired properties such as high flux whileminimizing undesirable properties such as low solubility or tendency tocause crystallization, rather than using only a single polymer, polymerswith different characteristics may be combined to realize superiorproperties. Therefore, in some embodiments, the pramipexole transdermalpatch of the present invention may comprise a combination of two or morepolymers. In one embodiment, the two polymers may comprise twoacrylate-based polymers. In addition, each polymer may comprise acarboxyl functional group, a hydroxyl functional group or bothfunctional groups.

However, when considering combining multiple polymers in a transdermalpatch, adequate miscibility between the polymers becomes important toavoid issues such as layering and phase separation. Experiments wereperformed to evaluate the miscibility of various combinations ofacrylate-based pressure sensitive adhesives. Some of the results aresummarized in Table 3.

TABLE 3 Polymer 1 90% (w/w) Polymer 2 10% (w/w) Observation DURO-TAK87-2054 DURO-TAK 87-2510 (hydroxyl Miscible (carboxyl functionalfunctional group) group) DURO-TAK 87-2054 DURO-TAK 87-4287 (hydroxylMiscible (carboxyl functional functional group) group)

Lag time is another important consideration for the daily pramipexoletransdermal patch of the present invention and can be influenced bypermeation enhancers.

Suitable enhancer compositions may include, but is not limited to,aliphatic alcohols, such as but not limited to saturated or unsaturatedhigher alcohols having 12 to 22 carbon atoms, such as oleyl alcohol andlauryl alcohol; saturated or unsaturated fatty acid having a chain of 8to 20 carbons, such as but not limited to linolic acid, oleic acid,linolenic acid, stearic acid, isostearic acid and palmitic acid; fattyacid esters, such as but not limited to isopropyl myristate, diisopropyladipate and isopropyl palmitate; alcohol amines, such as but not limitedto triethanolamine, triethanolamine hydrochloride anddiisopropanolamine; polyhydric alcohol alkyl ethers, such as but notlimited to alkyl ethers of polyhydric alcohols such as glycerol,ethylene glycol, propylene glycol, 1,3-butylene glycol, diglycerol,polyglycerol, diethylene glycol, polyethylene glycol, dipropyleneglycol, polypropylene glycol, sorbitan, sorbitol, isosorbide, methylglucoside, oligosaccharides and reducing oligosaccharides, where thenumber of carbon atoms of the alkyl group moiety in the polyhydricalcohol alkyl ethers is preferably 6 to 20; polyoxyethylene alkylethers, such as but not limited to polyoxyethylene alkyl ethers in whichthe number of carbon atoms of the alkyl group moiety is 6 to 20, and thenumber of repeating units (e.g. —OCH2CH2-) of the polyoxyethylene chainis 1 to 9, such as but not limited to diethylene glycol monoethyl ether,polyoxyethylene lauryl ether, polyoxyethylene cetyl ether,polyoxyethylene stearyl ether and polyoxyethylene oleyl ether;glycerides (i.e., fatty acid esters of glycerol), such as but notlimited to glycerol esters of fatty acids having 6 to 18 carbon atoms,where the glycerides may be monoglycerides (i.e., a glycerol moleculecovalently bonded to one fatty acid chain through an ester linkage),diglycerides (i.e., a glycerol molecule covalently bonded to two fattyacid chains through ester linkages), triglycerides (i.e., a glycerolmolecule covalently bonded to three fatty acid chains through esterlinkages), or combinations thereof, where the fatty acid componentsforming the glycerides include, but are not limited to octanoic acid,decanoic acid, dodecanoic acid, tetradecanoic acid, hexadecanoic acid,octadecanoic acid (i.e., stearic acid) and oleic acid; middle-chainfatty acid esters of polyhydric alcohols with aliphatic tails of 6-20carbon atoms; alkyl esters such as but not limited to lactic acid alkylesters and dibasic acid alkyl esters with chain of 1 to 6 carbon atoms;acylated amino acids; pyrrolidone; pyrrolidone derivatives; andcombinations thereof.

In certain embodiments, suitable enhancer compositions include, but arenot limited to ethoxylated fatty alcohols, such as but not limited topolyethylene glycol ethers, polyoxyethers of lauryl alcohol,polyethylene glycol ether of cetyl alcohol, polyethylene glycol ethersof stearic acid, polyethylene glycol ethers of oleyl alcohol,polyoxyethylene ethers of a mixture of cetyl alcohol and stearylalcohol, ethoxylated linear alcohol, and combinations thereof.

In certain embodiments, suitable enhancer compositions include, but arenot limited to lactic acid, tartaric acid, 1,2,6-hexanetriol, benzylalcohol, lanoline, potassium hydroxide (KOH), andtris(hydroxymethyl)aminomethane. Other suitable permeation enhancers maycomprise glycerol monooleate (GMO) and sorbitan monolaurate (SML),lactate esters such as lauryl lactate, methyl laurate, caproyl lacticacid, lauramide diethanolamine (LDEA), dimethyl lauramide, polyethyleneglycol-4 lauryl ether (Laureth-4), lauryl pyroglutamate (LP), sorbitanmonolaurate, ethanol and combinations thereof.

Permeation enhancers may also comprise surfactants includingcombinations of semi-polar solvents, e.g., propylene glycol, butanediol, N-methylpyrrolidone, dimethyl sulfoxide, diethylene glycol methylether and dimethyl isosorbide. Other surfactant permeation enhancers maycomprise isopropyl myristate, oleic acid, lauryl lactate andcombinations thereof.

Furthermore, in certain embodiments, permeation enhancer may comprisesqualane, isopropyl palmitate, isopropyl myristate, sorbitan laurate,DL-limonene, ethyl oleate, methyl dodecanoate, propylene glycoldicaprylocaprate, propylene glycol dicaprylate/dicaprate, Labrafac™ PG,octyl alcohol, dodecyl alcohol, polyoxyethylene (4) lauryl ether, Brij®30, oleyl alcohol, polyoxyethylene sorbitan monooleate, Tween®80,propylene glycol, diethylene glycol, monoethyl ether, propylene glycolmonocaprylate, Capryol PGMC, 1-methyl-2-pyrrolidinone, glyceryltriacetate, triacetin, polyoxyl castor oil, Kolliphor®RH40, oleoylmacrogol-6 glycerides, Labrafil™ M1944CS, linoleoyl polyoxyl-6glycerides, Labrafil™ M2125CS, caprylocaproyl macrogol-8 glycerides,Labrasol®, polyoxyl castor oil, oleoyl macrogol-6 glycerides, linoleoylpolyoxyl-6 glycerides, caprylocaproyl macrogol-8 glycerides and N-methylpyrrolidone.

Numerous permeation enhancers were evaluated to identify suitablepermeation enhancers, including permeation enhancers listed in Table 4below that lists solubility of pramipexole in the respective permeationenhancers. Preferred permeation enhancers that provide good solubilityinclude fatty acid such as oleic acid, saturated or unsaturated fattyalcohol having 8-26 carbon atoms such as octanol and oleyl alcohol,surfactants such as Tween 80 and Brij 30, and solvents such asTranscutal P, isopropyl alcohol, methanol, propylene glycol (PG) andethyl acetate.

TABLE 4 Solubility of Pramipexole Enhancer Category (mg/mL) Oleic AcidFatty acid 58.96 Methyl Laurate Fatty acid ester 7.07 Octanol Fattyalcohol 113.04 Oleyl Alcohol Fatty alcohol 113.04 Limonene Solvent 5.34Ethyl Acetate Solvent 34.28 Propylene Glycol (PG) Solvent 55.61 MethanolSolvent 100.08 Isopropyl Alcohol Solvent 106.67 Transcutal P Solvent121.99 Tween 80 Surfactants 86.07 Brij 30 Surfactants 111.14

Moreover, Example 2 and FIG. 2 detail some of our experimentation withvarious permeation enhancers using formulations F6-32 and F6-34 thatdiffer only in one permeation enhancer, namely F6-32 uses propyleneglycol whereas F6-34 uses Brij 30. As shown in FIG. 2, the difference inonly one permeation enhancer resulted in more than 30% difference incumulative permeated amount of pramipexole. Therefore, permeationenhancers can substantially influence the flux rate and lag time of thedaily transdermal patch of the present invention.

However, one major issue with permeation enhancers is that they cancause skin irritation. To minimize this problem, content of eachpermeation enhancer may be reduced without compromising permeationenhancing effects by combining two or more permeation enhancers.Therefore, in some embodiments, the pramipexole transdermal patch of thepresent invention comprises a combination of two or more permeationenhancers. In other embodiments, the pramipexole transdermal patch ofthe present invention comprises a combination of aliphatic alcohols,fatty acids, fatty acid esters, alcohol amines, polyhydric alcohol alkylethers, polyoxyethylene alkyl ethers, glycerides, middle-chain fattyacid esters of polyhydric alcohols, lactic acid alkyl esters, dibasicacid alkyl esters, acylated amino acids, pyrrolidone, pyrrolidonederivatives, ethoxylated fatty alcohols and/or surfactants. In anotherembodiment, the pramipexole transdermal patch of the present inventioncomprises a combination of fatty acids and/or fatty alcohols, such asoleic acid and lauric acid, oleic acid and lauryl alcohol, oleyl alcoholand lauric acid or oleyl alcohol, lauryl alcohol, surfactants or acombination thereof.

Importantly, in our experimentations with various combinations ofpermeation enhancers, we surprisingly found that combinations ofpermeation enhancers that provide higher flux also has higherpramipexole solubility. This finding is contrary to conventionalunderstanding that higher flux is typically associated with lowersolubility as discussed earlier in connection the Wiechers et al.reference. Specifically, combinations of permeation enhancers withpramipexole solubility greater than about 50 mg/mL provided higher fluxrate than those combinations with lower solubility. Therefore, in anembodiment, the daily pramipexole transdermal patch of the presentinvention comprises a combination of permeation enhancers withpramipexole solubility equal or higher than about 50 mg/mL.

Given the various properties of the polymers and permeation enhancer,numerous formulations were created using various combinations ofpolymers and permeation enhancers as listed in Table 5. As illustratedin the flux results summarized in Table 5, we found that certaincombinations result in potentiation that provide surprisingly high fluxrate.

TABLE 5 Formulation F6-20 F6-24 F6-31 F6-32 F6-33 F6-34 F6-35 F6-36DT504B DT502B DT2054 37.5 40 38.5 27 29 27 41 41 (—COOH) DT2852 (—COOH)DT2510 37.5 40 41 41 (—OH) DT4287 38.5 50 53 50 (—OH) Pramipexole 10 108 8 8 8 8 8 Base Methyl 10 10 10 10 laurate Proplyene 5 5 5 glycolTranscutol P 5 5 Brij 30 5 5 5 5 Ethyl Oleate 5 Oleic acid 5 Isopropyl 5Myristate Lauryl 5 Alcohol Flux rate 9.3 10 6.9 8.6 7.5 6.3 2.3 4.7(μg/cm²-hr)

As Table 5 illustrates, formulations F6-20, F6-24, F6-31, F6-32, F6-33,F6-34, F6-35 and F6-36 each exhibit steady state pramipexole flux ratein a range of about 2.3 to about 10 μg/cm²-hr, all above the desiredminimum flux rate of about 0.8 μg/cm²-hr. Surprisingly, each of theformulations comprises a carboxyl group-containing acrylic polymer incombination with a hydroxyl group-containing acrylic polymer. These highflux rates are in stark contrast to substantially lower flux rate forformulations that we tested that do not comprise a carboxylgroup-containing acrylic polymer in combination with a hydroxylgroup-containing acrylic polymer. In many cases, the difference in fluxrates are more than an order of magnitude lower. This indicates that acarboxyl group-containing acrylic polymer in combination with a hydroxylgroup-containing acrylic polymer result in potentiation. For example,Duro-Tak™ 87-2054 containing acrylic polymer with carboxyl functionalgroup, in combination with an acrylic polymer with hydroxyl functionalgroup results in potentiation with respect to achieving high flux rate.In addition, these formulations avoided crystallization and miscibilityissues while providing desired flux rate, demonstrating proper selectionand proportion of various components. In addition, Example 3 and FIG. 3illustrate that the two formulations with the highest flux rate F-20 andF-24 each have lag time of about 3 to 4 hour, after which they are ableto maintain up to about 30 hours of steady pramipexole bloodconcentration. It is notable that the Reference Sifrol® tablets provideda substantially greater fluctuation in blood concentration. Furthermore,as shown in Table 6, both formulations F-20 and F-24 have good stabilitycharacteristics. Specifically, after storage at 60° C. at 75% relativehumidity for 14 days, both formulations contain substantially less than1% WW impurities.

TABLE 6 Impurities (% W/W) ACBR¹ Test Assay RRT RRT RRT RRT RRT TotalFormulation # Stress Condition Interval % w/w 0.3 0.41 0.43 0.52 0.62impurities F6-20 60° C./75% RH Initial 106.5 0.04 — 0.05 — 0.1 0.19  7Days 110.54 0.05 0.09 0.09 — 0.15 0.37 14 Days 110.51 — 0.11 0.07 — 0.150.33 F6-24 60° C./75% RH Initial 95.4 — 0.1  0.09 — 0.13 0.33  7 Days95.46 — 0.06 0.06 — 0.11 0.23 14 Days 94.23 0.03 — 0.03 — 0.06 0.13

Therefore, in an embodiment, the pramipexole transdermal patch of thepresent invention comprises a carboxyl group-containing acrylic polymerin combination with hydroxyl group-containing acrylic polymer. Morespecifically, the pramipexole transdermal patch of the present inventioncomprises polymers sourced from Duro-Tak™ 87-2054 in combination withpolymers sourced from Duro-Tak™ 87-2510 or Duro-Tak™ 87-4287.

In some embodiments, the weight ratio of the content of the carboxylgroup-containing acrylic adhesive to the content of the hydroxylgroup-containing acrylic adhesive is from about 5:1 to about 1:5;preferably from about 4:1 to about 1:4; more preferably from about 3:1to about 1:3; and even more preferably from about 2:1 to about 1:2.

In other embodiments, the pramipexole is in a free base form. The amountof pramipexole in the matrix is from about 2 to about 10%; preferablyfrom about 4 to about 10%; more preferably from about 6 to about 10%;and even more from about 8 to about 10%.

In some embodiments, the permeation enhancers, comprise aliphaticalcohols, fatty acids, fatty acid esters, alcohol amines, polyhydricalcohol alkyl ethers, polyoxyethylene alkyl ethers, glycerides,ethoxylated fatty alcohols, or a combination thereof. In otherembodiments, the permeation enhancers comprise methyl laurate, propyleneglycol, transcutol P, brij 30, ethyl oleate, oleic acid, isopropylmyristate, lauryl alcohol, surfactants or a combination thereof.

The total amount of the permeation enhancers in the matrix may comprisefrom about 10 to about 15%. In some embodiments, the pramipexoletransdermal patch of the present invention comprises two permeationenhancers in a total amount of 10% of the matrix. In some embodiments,the pramipexole transdermal patch of the present invention comprises twopermeation enhancers in a total amount of about 15% of the matrix. Insome embodiments, the pramipexole transdermal patch of the presentinvention comprises three permeation enhancers in a total amount of 15%of the matrix.

In some embodiments, the pramipexole transdermal patch of the presentinvention comprises a combination of methyl laurate and propylene glycolpermeation enhancers wherein the weight ratio of the content of methyllaurate to the content of propylene glycol is about 2:1.

In some embodiments, the pramipexole transdermal patch of the presentinvention comprises a combination of Transcutol P and Brij 30 whereinthe weight ratio of the content of Transcutol P to the content of Brij30 is preferably about 1:1.

In some embodiments, the pramipexole transdermal patch of the presentinvention comprises a combination of ethyl oleate and oleic acid whereinweight ratio of the content of ethyl oleate to the content of oleic acidis preferably about 1:1.

In some embodiments, the pramipexole transdermal patch of the presentinvention comprises a combination of isopropyl myristate and laurylalcohol wherein the weight ratio of the content of isopropyl myristateto the content of lauryl alcohol is preferably about 1:1.

In some embodiments, the pramipexole transdermal patch of the presentinvention comprises a combination of propylene glycol, Transcutol P andBrij 30 wherein the weight ratio of the content of propylene glycol tothe content of Transcutol P to the content of Brij 30 is preferablyabout 1:1:1.

II. Preparation of Pramipexole Transdermal Patch

The pramipexole transdermal patch may be formulated in accordance withprocedures disclosed in the prior art such as CN 103432,104; USpublication 2016/0113908 and Tingting et al. AAPS Pharma Sci Tech (2016)published online May 31, 2016, the disclosures of which are incorporatedherein by reference.

For example, the daily pramipexole transdermal patch of the presentinvention may be made by preparing a blend of an appropriate amount ofone or more polymer solutions such as Duro-Tak™ 87-2054, Duro-Tak™87-2510 or Duro-Tak™ 87-4287. These polymer solutions may comprisesolvents such as ethyl acetate, heptane, n-heptane, hexane methanol,ethanol, isopropanol, 2,4-pentanedione, toluene, xylene or a combinationthereof. Next, pramipexole or a pharmaceutically acceptable saltthereof, permeation enhancers as well as tackifier are added to theblend. Importantly, the blend should have viscosity of between about 0.1to 18 Pascal seconds (Pa-s), as low viscosity prevents formation of thedrug-containing layer and high viscosity can create a drug containinglayer of uneven thickness with uneven distribution of the drug.

The blend is then cast onto a release liner for drying at appropriatedrying conditions to form the drug-containing layer. During the dryingprocess, the solvent(s) are evaporated so that only a trace remains.After the drying process, the drug-containing layer is then laminated onone side onto a backing film while a release liner is applied onto theother side of the drug-containing layer.

III. Uses of Pramipexole Transdermal Patch

On application to the skin, the pramipexole in the matrix of the patchdiffuses into the skin where it is absorbed into the bloodstream toproduce a systemic drug effect. The onset of the drug effect depends onvarious factors, such as, potency of the pramipexole, the solubility anddiffusivity of the pramipexole in the skin, thickness of the skin,concentration of the pramipexole within the skin application site,concentration of the pramipexole in the matrix, and the like. The dailypramipexole transdermal patch of the present invention is kept on theskin for 24 hours without removal until the end of the 24-hour period atwhich point a new daily pramipexole transdermal patch of the presentinvention is applied soon after to minimize fluctuations in pramipexoleblood concentration.

The representative examples which follow are intended to help illustratethe invention, and are not intended to, nor should they be construed to,limit the scope of the invention. Indeed, various modifications of theinvention and many further embodiments thereof, in addition to thoseshown and described herein, will become apparent to those skilled in theart from the full contents of this document, including the exampleswhich follow and the references to the scientific and patent literaturecited herein. It should further be appreciated that, unless otherwiseindicated, the entire contents of each of the references cited hereinare incorporated herein by reference to help illustrate the state of theart. The following examples contain important additional information,exemplification and guidance which can be adapted to the practice ofthis invention in its various embodiments and the equivalents thereof.

These and other aspects of the present invention will be furtherappreciated upon consideration of the following Examples, which areintended to illustrate certain particular embodiments of the inventionbut are not intended to limit its scope, as defined by the claims.

EXAMPLES Example 1: In Vitro Skin Permeation Studies—Effect ofPressure-Sensitive Adhesives

Flux rate of the pramipexole transdermal patch of the present inventionis measured with a standard procedure using Franz diffusion cells andhuman cadaver skin as described in Strasinger C., Raney S., Tran D.,Ghosh P., Newman B., Bashaw E., Ghosh T. and Shukla C., Navigatingsticky areas in transdermal product development, Journal of ControlledRelease: 233 (2016) 1-9.

Specifically, in each Franz diffusion cell a disc (diameter of 25 mm) ofhuman cadaver skin is placed on the receptor compartment. A transdermaldelivery system is cut the same size as the skin and placed over thediffusion area in the center of the receptor. The donor compartment isthen added and clamped to the assembly. At time 0, receptor mediumsolution 14 mL is added into the receptor compartment and the cellmaintained at 32° C. Samples of the receptor compartment are takenperiodically to determine the skin flux and analyzed by HPLC. Thepramipexole concentration in the sampled solution was assayed by HPLC,and the flux value (value of the skin permeation rate of the drug in asteady state) and 24-hour cumulative permeation were calculated.

Various formulations were prepared according to the transdermal patchpreparation procedures described above. FIG. 1 plots the cumulativepermeated amount for transdermal patch made from Duro Tak 87-2852, DuroTak 87-2510, Duro Tak 87-2054 and Duro Tak 87-4287. As FIG. 1illustrates, various polymers result in vastly different cumulativepermeation. It is notable that polymers with hydroxyl functional grouptends to provide higher flux rate compared to polymers with carboxylfunctional group.

Example 2: In Vitro Skin Permeation Studies—Effect of PermeationEnhancers

Cumulative permeated amount for formulations F6-32 and F6-34 is obtainedusing the same method as described in Example 1 with results shown inTable 4. Both formulations comprise the same components except for thepermeation enhancer. Specifically, both formulations comprisepramipexole free base 8% (w/w), DT2054 27% (w/w) and DT4287 50% (w/w).However, formulation F6-32 comprises methyl laurate 10% (w/w) andpropylene glycol 5% (w/w) as permeation enhancers whereas formulationF6-34 comprises methyl laurate 10% (w/w) and Brij 30 5% (w/w) aspermeation enhancers. Cumulated permeated amount of pramipexole in thein-vitro skin permeation study during 24 hours was 0.221 mg/cm² forF6-32, and 0.165 mg/cm² for F6-34, a difference of over 30% thatdemonstrate the significant influence of permeation enhancers on fluxrate and lag time.

Example 3: Pharmacokinetics of Pramipexole Transdermal Patch

The pharmacokinetics studies of formulations F6-20 and F6-24 wereassessed in 12 healthy volunteers. The transdermal system is applied tohealthy subjects topically on their upper chest for a day. The bloodsamples were collected periodically.

The mean pramipexole plasma concentration in ng/mL versus time in hoursof two test formulations F6-20 and F6-24 as well as the reference,Sifrol 0.375 ER tablet, are shown in FIG. 3. As FIG. 3 illustrates,formulations F6-20 and F6-24 both have lag time of about 4 and about 3hours respectively, which are within the desired about 8 hours or less.In addition, F6-20 and F6-24 are able to provide substantially stableplasma concentration at about 0.2 ng/mL and 0.8 ng/mL, respectively, formore than 20 hours after the initial lag time. In contrast, the resultsshow that Sifrol tablet provides large fluctuation in plasmaconcentration tracing out a parabola over the same period on the samefigure.

Although the present invention has been described in terms of specificexemplary embodiments and examples, it can be appreciated by thoseskilled in the art that changes could be made to the examples describedabove without departing from the broad inventive concept thereof. It isunderstood, therefore, that this invention is not limited to theparticular examples disclosed, but it is intended to cover modificationswithin the spirit and scope of the present invention as defined by theappended claims.

It is to be understood that both the foregoing general description andthe following detailed description are exemplary and explanatory onlyand are not restrictive of the invention, as claimed.

These and other changes can be made to the technology in light of thedetailed description. In general, the terms used in the followingdisclosure should not be construed to limit the technology to thespecific embodiments disclosed in the specification, unless the abovedetailed description explicitly defines such terms. Accordingly, theactual scope of the technology encompasses the disclosed embodiments andall equivalent ways of practicing or implementing the technology.

What is claimed is:
 1. A transdermal patch for daily administrationcomprising: (i) a drug-containing layer; (ii) a backing layer; and (iii)a protective layer, wherein the drug-containing layer comprises (a)pramipexole or a pharmaceutically acceptable salt thereof, (b) acombination of at least two permeation enhancers, wherein thecombination is selected from the group consisting of: 1) methyl laurateand propylene glycol in a weight ratio of about 2:1; 2) diethyleneglycol monoethyl ether and polyoxyethylene(4)lauryl ether in a weightratio of about 1:1; 3) methyl laurate and polyoxyethylene(4)lauryl etherin a weight ratio of about 2:1; and 4) propylene glycol, diethyleneglycol monoethyl ether and polyoxyethylene(4)lauryl ether in a weightratio of about 1:1:1; (c) a carboxyl functional group containingacrylic-based polymer comprising an acrylate copolymer of 2-ethylhexylacrylate, vinyl acetate, butyl acrylate, acrylic acid and a crosslinker;and (d) a hydroxyl functional group containing acrylic-based polymercomprising an acrylate copolymer of 2-ethylhexyl acrylate, methylacrylate and 2-hydroxyethyl acrylate or an acrylate copolymer of2-ethylhexyl acrylate, vinyl acetate and 2-hydroxyethyl acrylate;wherein the carboxyl group-containing acrylic-based polymer and thehydroxyl group-containing acrylic-based polymer are in a ratio of fromabout 2:1 to about 1:2 by weight, wherein the transdermal patch providesflux rate of between about 6.3 μg/cm² hr and about 10 μg/cm² hr for upto about 40 hours and wherein at least one permeation enhancer haspramipexole solubility of between about 50 mg/mL to about 122 mg/mL. 2.The transdermal patch of claim 1, wherein the pramipexole or itspharmaceutically acceptable salt thereof is selected from pramipexolefree-base, pramipexole dihydrochloride or dexpramipexole.
 3. Thetransdermal patch of claim 1, wherein the pramipexole or itspharmaceutically acceptable salt thereof is in an amount from about 2%to about 15% by weight of the drug-containing layer.
 4. The transdermalpatch of claim 1, wherein lag time for the transdermal patch is about 8hours or less.
 5. The transdermal patch of claim 1, wherein impuritylevel within pramipexole is about 1.0% or less by weight after up toabout 2 weeks of storage, up to about 60° C., and up to about 75%relative humidity.
 6. A method for treating Parkinson's disease,restless leg syndrome, migraine headaches or ALS comprising the step ofadministering the transdermal patch of claim 1 to a human subject inneed thereof through the human's skin for a period of about 24 hourswherein the transdermal patch comprises a therapeutcially effectiveamount of pramipexole or its pharmaceutically acceptable salt.
 7. Themethod of claim 6, wherein the total delivered amount of pramipexole isfrom about 0.2 mg to about 10 mg daily.
 8. The transdermal patch ofclaim 1, wherein each acrylic-based polymer has pramipexole solubilitybetween about 5% to about 10%.
 9. The transdermal patch of claim 1,wherein the transdermal patch provides flux rate of between about 9.3μg/cm² hr and about 10 μg/cm2 hr for up to about 40 hours.
 10. Thetransdermal patch of claim 1, wherein the carboxyl group-containingacrylic-based polymer and the hydroxyl group-containing acrylic-basedpolymer are in a ratio of about 1:1 by weight.
 11. The transdermal patchof claim 1, wherein the combination of at least two permeation enhancersis methyl laurate and propylene glycol.
 12. The transdermal patch ofclaim 1, wherein the combination of at least two permeation enhancers isselected from diethylene glycol monoethyl ether andpolyoxyethylene(4)lauryl ether or propylene glycol, diethylene glycolmonoethyl ether, and polyoxyethylene(4) lauryl ether.
 13. The method ofclaim 6, wherein the carboxyl group-containing acrylic-based polymer andthe hydroxyl group-containing acrylic-based polymer are in a ratio ofabout 1:1 by weight.
 14. A transdermal patch for daily administrationcomprising: a drug-containing layer (ii) a backing layer; and (iii) aprotective layer wherein the drug-containing layer comprises (a)pramipexole or a pharmaceutically acceptable salt thereof, (b) acombination of at least two permeation enhancers, wherein thecombination is selected from the group consisting of: 1) methyl laurateand propylene glycol in a weight ratio of about 2:1; 2) diethyleneglycol monoethyl ether and polyoxyethylene(4)lauryl ether in a weightratio of about 1:1; 3) methyl laurate and polyoxyethylene(4)lauryl etherin a weight ratio of about 2:1; and 4) propylene glycol, diethyleneglycol monoethyl ether and polyoxyethylene(4)lauryl ether in a weightratio of about 1:1:1; (c) a carboxyl functional group containingacrylic-based polymer comprising an acrylate copolymer of 2-ethylhexylacrylate, vinyl acetate, butyl acrylate, acrylic acid and a crosslinker;and (d) a hydroxyl functional group containing acrylic-based polymercomprising an acrylate copolymer of 2-ethylhexyl acrylate, methylacrylate and 2-hydroxyethyl acrylate or an acrylate copolymer of2-ethylhexyl acrylate, vinyl acetate and 2-hydroxyethyl acrylate;wherein the carboxyl group-containing acrylic-based polymer and thehydroxyl group-containing acrylic-based polymer are in a ratio of fromabout 2:1 to about 1:2 by weight, wherein lag time for the transdermalpatch is between about 3 and about 4 hours and wherein at least onepermeation enhancer has pramipexole solubility of between about 50 mg/mLand about 122 mg/mL.
 15. The transdermal patch of claim 14, wherein thepramipexole or its pharmaceutically acceptable salt thereof is selectedfrom comprises pramipexole free-base, pramipexole dihydrochloride ordexpramipexole.
 16. The transdermal patch of claim 14, wherein thepramipexole or its pharmaceutically acceptable salt thereof is in anamount from about 2% to about 15% by weight of the drug-containinglayer.
 17. The transdermal patch of claim 14, wherein the transdermalpatch provides flux rate of between about 6.3 μg/cm² hr and about 10μg/cm² hr for up to about 40 hours.
 18. The transdermal patch of claim14, wherein impurity level within pramipexole is about 1.0% or less byweight after up to about 2 weeks of storage, up to about 60° C., and upto about 75% relative humidity.
 19. The transdermal patch of claim 14,wherein each acrylic-based polymer has pramipexole solubility betweenabout 5% to about 10%.
 20. The transdermal patch of claim 14, whereinthe transdermal patch provides flux rate of between about 9.3 μg/cm² hrand about 10 μg/cm2 hr for up to about-40 hours.
 21. A method fortreating Parkinson's disease, restless leg syndrome, migraine headachesor ALS comprising the step of administering the transdermal patch ofclaim 14 to a human subject in need thereof through the human's skin fora period of about 24 hours wherein the transdermal patch comprises atherapeutically effective amount of pramipexole or its pharmaceuticallyacceptable salt.
 22. The method of claim 21, wherein the total deliveredamount of pramipexole is from about 0.2 mg to about 10 mg daily.
 23. Thetransdermal patch of claim 14, wherein the carboxyl group-containingacrylic-based polymer and the hydroxyl group-containing acrylic-basedpolymer are in a ratio of about 1:1 by weight.
 24. The transdermal patchof claim 14, wherein the combination of at least two permeationenhancers is methyl laurate and propylene glycol.
 25. The transdermalpatch of claim 14, wherein the combination of at least two permeationenhancers is diethylene glycol monoethyl ether andpolyoxyethylene(4)lauryl ether or propylene glycol, diethylene glycolmonoethyl ether, and polyoxyethylene(4) lauryl ether.